Effect of antifibrotic agents on postoperative complications after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Antifibrotic agents (AFAs) are now standard-of-care for idiopathic pulmonary fibrosis (IPF). Concerns have arisen about the safety of these drugs in patients undergoing lung transplantation (LTx). METHODS: We performed a multi-centre, nationwide, retrospective, observational study of French IPF patients undergoing LTx between 2011 and 2018 to determine whether maintaining AFAs in the peri-operative period leads to increased bronchial anastomoses issues, delay in skin healing and haemorrhagic complications. We compared the incidence of post-operative complications and the survival of patients according to AFA exposure. RESULTS: Among 205 patients who underwent LTx for IPF during the study period, 58 (28%) had received AFAs within 4 weeks before LTx (AFA group): pirfenidone in 37 (18.0%) and nintedanib in 21 (10.2%). The median duration of AFA treatment before LTx was 13.8 (5.6-24) months. The AFA and control groups did not significantly differ in airway, bleeding or skin healing complications (p = 0.91, p = 0.12 and p = 0.70, respectively). Primary graft dysfunction was less frequent in the AFA than control group (26% vs. 43%, p = 0.02), and the 90-day mortality was lower (7% vs. 18%, p = 0.046). CONCLUSIONS: AFA therapy did not increase airway, bleeding or wound post-operative complications after LTx and could be associated with reduced rates of primary graft dysfunction and 90-day mortality.

Eltrombopag for Post-Transplant Poor Graft Function in East Asian Patients.

Poor graft function (PGF) is a serious, potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Eltrombopag has shown multilineage responses in patients with refractory severe aplastic anemia, supporting the idea that it may improve cytopenia in patients with PGF. This retrospective, single center analysis included 8 Korean patients receiving eltrombopag for PGF. Median interval between transplant and eltrombopag treatment was 73 days, and the median duration treatment was 3.5 weeks. With median maximum daily dose of 50 mg, the time to best response was 93 days. Median hemoglobin increased from 8.2 g/dL to 10.9 g/dL, platelet from 18.5 × 109/L to 54 × 109/L, and absolute neutrophil count from 1.25 × 109/L to 3.32 × 109/L. In conclusion, eltrombopag is a good option for PGF in Korean patients, even at a lower dose compared to western patients.

New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation.

Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.

Eltrombopag for the treatment of poor graft function following allogeneic stem cell transplant: a retrospective multicenter study.

This retrospective study assessed the effectiveness of eltrombopag (EPAG), a thrombopoietin receptor agonist, in the treatment of poor graft function (PGF) following an allogeneic haemopoietic stem cell transplantation (HSCT). Complete response was defined as normalization of blood counts, whereas partial response was defined as transfusion independence. A total of 48 patients with full donor chimerism after HSCT, received EPAG for a median of 120 days (range 10-591). Patients with uni- bi- or tri-lineage cytopenia started treatment at a median of 95 days (range 17-877) after HSCT. The overall response rate was 75%: 24 patients had a complete response and 12 had a partial response. Positive predictors of response were an HLA-matched donor, a CD34+ dose at transplant > 4 × 106/kg, and starting EPAG treatment at least 90 days after HSCT. Patients with more than one positive predictor had a response rate of 92% for the overall patient cohort and 94% for patients with tri-lineage cytopenia. One-year survival was 89% for complete responders, 60% for partial responders and 20% for non-responders (p = 0.0004). EPAG improves peripheral blood counts in patients with poor graft function following HSCT. Response to EPAG can be predicted and has a significant impact on survival.

Levosimendan for Treatment of Primary Graft Dysfunction After Heart Transplantation: Optimal Timing of Application.

OBJECTIVES: Primary graft dysfunction remains a serious problem after heart transplant. Pharmacological treatment with the calcium sensitizer levosimendan may be an additive treatment for primary graft dysfunction. MATERIALS AND METHODS: Patients undergoing heart transplant between 2010 and 2020 were retrospectively reviewed and divided depending on postoperative treatment with (n = 41) or without (n = 109) levosimendan. Recipients who received levosi mendan were further divided with regard to timing of levosimendan application (early group: started ≤48 hours posttransplant [n = 23]; late group: started >48 hours posttransplant [n = 18]). RESULTS: Patients who received levosimendan treatment displayed a remarkable incidence (87.8%) of postoperative primary graft dysfunction with need for venoarterial extracorporeal membrane oxygenation and therefore often presented with perioperative morbidity. Patient with early application of levosimendan showed significantly decreased duration of venoarterial extracorporeal membrane oxygenation support (5.1 ± 3.5 days vs 12.6 ± 9.3 days in those with late application; P < .01) and decreased mortality during venoarterial extracorporeal membrane oxygenation support (0.0% vs 33.3% in early vs late group; P < .01). In addition, compared with patients with late levosimendan application, patients with early application needed fewer blood transfusions (P < .05), had shorter ventilation times (279 ± 235 vs 428 ± 293 h; P = .03), and showed a trend of reduced incidence of postoperative renal failure (69.6% vs 94.4%; P = .06). Moreover, survival analyses indicated an increased survival for patients with early start of levosimendan therapy within the first 48 hours after heart transplant (P = .09). CONCLUSIONS: Pharmacotherapy with levosimendan may be a promising additive in the treatment of primary graft dysfunction after heart transplant. With administration of levosimendan within the first 48 hours posttransplant, rates of successful weaning from venoarterial extracorporeal membrane oxygenation and outcomes after heart transplant were shown to increase.

PACAP neuropeptide promotes Hepatocellular Protection via CREB-KLF4 dependent autophagy in mouse liver Ischemia Reperfusion Injury.

Organ ischemia reperfusion injury (IRI), associated with acute hepatocyte death, remains an unresolved problem in clinical orthotopic liver transplantation (OLT). Autophagy, an intracellular self-digesting progress, is responsible for cell reprograming required to regain post-stress homeostasis. Methods: Here, we analyzed the cytoprotective mechanism of pituitary adenylate cyclase-activating polypeptide (PACAP)-promoted hepatocellular autophagy in a clinically relevant mouse model of extended hepatic cold storage (4 °C UW solution for 20 h) followed by syngeneic OLT. Results: In contrast to 41.7% of liver graft failure by day 7 post-transplant in control group, PACAP treatment significantly improved graft survival (91.7% by day 14), and promoted autophagy-associated regeneration programs in OLT. In parallel in vitro studies, PACAP-enhanced autophagy ameliorated cellular damage (LDH/ALT levels), and diminished necrosis in H2O2-stressed primary hepatocytes. Interestingly, PACAP not only induced nuclear cAMP response element-binding protein (CREB), but also triggered reprogramming factor Kruppel-like factor 4 (KLF4) expression in IR-stressed OLT. Indeed, CREB inhibition attenuated hepatic autophagy and recreated hepatocellular injury in otherwise PACAP-protected livers. Furthermore, CREB inhibition suppressed PACAP-induced KLF4 expression, whereas KLF4 blockade abolished PACAP-promoted autophagy and neutralized PACAP-mediated hepatoprotection both in vivo and in vitro. Conclusion: Current study documents the essential neural regulation of PACAP-promoted autophagy in hepatocellular homeostasis in OLT, which provides the emerging therapeutic principle to combat hepatic IRI in OLT.

Nitrite attenuates mitochondrial impairment and vascular permeability induced by ischemia-reperfusion injury in the lung.

Primary graft dysfunction (PGD) is directly related to ischemia-reperfusion (I/R) injury and a major obstacle in lung transplantation (LTx). Nitrite (NO2-), which is reduced in vivo to form nitric oxide (NO), has recently emerged as an intrinsic signaling molecule with a prominent role in cytoprotection against I/R injury. Using a murine model, we provide the evidence that nitrite mitigated I/R-induced injury by diminishing infiltration of immune cells in the alveolar space, reducing pulmonary edema, and improving pulmonary function. Ultrastructural studies support severe mitochondrial impairment in the lung undergoing I/R injury, which was significantly protected by nitrite treatment. Nitrite also abrogated the increased pulmonary vascular permeability caused by I/R. In vitro, hypoxia-reoxygenation (H/R) exacerbated cell death in lung epithelial and microvascular endothelial cells. This contributed to mitochondrial dysfunction as characterized by diminished complex I activity and mitochondrial membrane potential but increased mitochondrial reactive oxygen species (mtROS). Pretreatment of cells with nitrite robustly attenuated mtROS production through modulation of complex I activity. These findings illustrate a potential novel mechanism in which nitrite protects the lung against I/R injury by regulating mitochondrial bioenergetics and vascular permeability.

Discontinuing amiodarone treatment prior to heart transplantation lowers incidence of severe primary graft dysfunction.

BACKGROUND: Recent studies have shown an increased incidence of primary graft dysfunction (PGD) in patients treated with amiodarone prior to orthotopic heart transplant (OHT). We hypothesized that discontinuation of amiodarone before OHT may lower the incidence of severe PGD. METHODS: This was a single-center retrospective study of 381 adult OHT recipients between January 2010 and June 2017. Within 6 months prior to OHT, 197 did not receive amiodarone (Group 1), 142 continued amiodarone to OHT (Group 2), and 42 had amiodarone treatment discontinued before OHT (Group 3). RESULTS: 53 (13.9%) participants developed severe PGD, 13 (6.6%) of which were in Group 1, 36 (25.4%) were in Group 2, and 4 (9.5%) were in Group 3 (P < .001). Multivariable analysis revealed continued amiodarone treatment to OHT (Group 2; OR, 3.70; 95% CI, 1.26-10.88; P = .018) to be an independent risk factor for the development of severe PGD when Group 1 served as the reference group. Moreover, patients in Group 3 had no difference in the risk of severe PGD (OR = 0.416, 95% CI = 0.08-2.15; P = .296). CONCLUSION: We found that discontinuing amiodarone treatment prior to OHT resulted a lower incidence of severe PGD.

Platelet and liver regeneration after liver surgery.

The success of liver surgery, including resection and transplantation, is largely dependent on the ability of the liver to regenerate. Despite substantial improvement in surgical techniques and perioperative care, one of the main concerns is post-hepatectomy liver failure and early allograft dysfunction, both of which are associated with impaired liver regeneration. Recent studies have demonstrated the positive role of platelets in promoting liver regeneration and protecting hepatocytes; however, the underlying mechanisms responsible for these effects are not fully understood. In this review, we updated the accumulated evidence of the role of platelets in promoting liver regeneration, with a focus on liver resection and liver transplantation. The goal of these studies was to support the clinical implementation of platelet agents, such as thrombopoietin receptor agonists, to augment liver regeneration after liver surgery. This "platelet therapy" may become a treatment choice for post-hepatectomy liver failure and early allograft dysfunction.

Acetyl-3-Aminoethyl Salicylate Ameliorates Hepatic Ischemia/Reperfusion Injury and Liver Graft Survival Through a High-Mobility Group Box 1/Toll-Like Receptor 4-Dependent Mechanism.

In liver transplant cases, severe hepatic ischemia/reperfusion injury (HIRI) is a strong predictor of adverse liver graft and overall outcomes. During HIRI, high-mobility group box 1 (HMGB1) promotes hepatocellular death and proinflammatory cytokine secretion by toll-like receptor 4 (TLR4). Because salicylates inhibit HMGB1/TLR4 interaction, we hypothesized that salicylates may ameliorate HIRI-induced liver damage by inhibiting HMGB1/TLR4 axis activation. Using a murine model of HIRI, we found that the salicylate acetyl-3-aminoethyl salicylic acid (ac3AESA) reduced serum alanine aminotransferase and aspartate aminotransferase as well as Suzuki scores and apoptotic cell counts after HIRI. Ac3AESA also down-regulated hepatocellular HMGB1 and TLR4 expression, phosphorylated inhibitor of κBα, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, cleaved caspase 3, and cleaved caspase 1 levels after HIRI. Ac3AESA reduced liver Kupffer cell transcription of proinflammatory mediators tumor necrosis factor α (TNF-α), interleukin (IL) 6, IL1ß, chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2, and CXCL8 after HIRI. Ac3AESA also dose-dependently reduced in vitro release of Kupffer cell TNF-α. Employing a murine orthotopic liver transplantation model, we found daily ac3AESA administration up to day 10 after transplant improved liver graft survival, suppressed allograft damage, and down-regulated HMGB1/TLR4 signaling. These benefits to survival and allograft health were maintained for cold ischemia times of 12 and 18 hours. Notably, TLR4 knockout eliminated all foregoing ac3AESA-induced effects. In conclusion, ac3AESA partially rescues the negative effects of HIRI and prolongs liver graft survival in a TLR4-dependent manner.

Staphylococcus Infection-Associated Glomerulonephritis in a Kidney Transplant Patient: Case Report.

BACKGROUND: Staphylococcus infection-associated glomerulonephritis is a rare cause of graft dysfunction in kidney transplant. Suspicion should be high in the setting of elevation of serum creatinine, active urinary sediment, with or without hypocomplementemia, and simultaneous Staphylococcus aureus infection. A kidney biopsy is usually diagnostic. CASE REPORT: A 56-year-old man, who received a kidney transplant in 1998, with basal serum creatinine of 1.2 mg/dL and normal urinary sediment, was admitted to our kidney transplantation unit with graft dysfunction and a urinary tract infection caused by S aureus with septicemia, treated with antibiotics, in the context of recently intensified immunosuppression for a primary immune thrombocytopenia diagnosed 3 weeks earlier. After antibiotic treatment, the patient persisted with graft dysfunction, edema, and hypertension, with a S aureus isolation in the urine culture, active urinary sediment, and low C3. A kidney biopsy was performed, showing diffuse proliferative endocapillary and mesangial glomerulonephritis, with IgA(++) and C3(++) mesangial and endocapillary deposits in immunofluorescence. The patient was treated symptomatically and maintained his regular immunosuppression. At the last follow-up, his serum creatinine value was stable at 2.5 mg/dL. CONCLUSIONS: The onset of a nephritic syndrome with a simultaneous S aureus infection should lead to suspicion of this uncommon entity, confirmed histologically. Despite its association with poor graft survival, our patient's graft survival remained stable.

Immunosuppression: Have We Learnt Anything?

Outcomes after lung transplantation remain disappointing because there is a high incidence of chronic lung allograft dysfunction (CLAD), which typically follows a progressive clinical course and often results in allograft failure and death. Chronic rejection is considered the predominant cause of CLAD. Thus, optimal immunosuppression has been viewed as having the potential to prevent CLAD and improve survival after lung transplantation. Numerous clinical trials have been conducted investigating the efficacy and safety of various immunosuppressive agents. Many studies have been small and single-center clinical trials but some have been international and multicenter trials enrolling more than 300 patients. This review focuses on clinical trials of immunosuppression conducted in lung transplantation and points out strengths and limitations of the various studies. Ultimately, the findings of these clinical trials explain the current state of practice in lung transplantation and identify gaps in knowledge that require additional study. Finally, there is an ongoing need for carefully designed and conducted clinical trials to improve clinical practice and outcomes after lung transplantation.

Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation.

BACKGROUND: There is growing concern regarding the association between pre-transplant amiodarone exposure and post-transplant adverse outcomes. We hypothesized that amiodarone use would be associated with the development of severe primary graft dysfunction (PGD) in a dose-dependent manner. METHODS: This was a retrospective review of 269 adult orthotopic heart transplantation (OHT) recipients at our institution between 2010 and 2014. At the time of OHT, 100 were receiving amiodarone therapy (Group 1) and 169 were not (Group 2). RESULTS: Pre-OHT creatinine was higher in Group 1 (1.49 ± 0.63 vs 1.27 ± 0.68 mg/dl, p = 0.011). At time of listing, Group 1 had higher frequency of status 2 (42.0% vs 29.0%), and Group 2 had higher frequency of status 1A (20.7% vs 8.0%; p = 0.009). Severe PGD (mechanical circulatory support within 24 hours post-OHT) was significantly higher in Group 1 (20.0% vs 5.3%, p < 0.001). Pre-OHT amiodarone use was an independent risk factor for severe PGD (odds ratio [OR], 6.05; 95% confidence interval [CI], 2.47-14.83; p < 0.001) and in-hospital mortality (OR, 2.88; 95% CI, 1.05-7.88; p = 0.039) in multivariable analysis. Each 100-mg increase in the day-of-OHT amiodarone dose (OR, 1.55; 95% CI, 1.26-1.90) and each 18,300-mg increase in the 6-month cumulative dose (OR, 1.67; 95% CI, 1.31-2.15) was associated with increased odds of developing severe PGD (p < 0.001 for both). CONCLUSIONS: Amiodarone use pre-OHT is independently associated with increased incidence of severe PGD and in-hospital mortality and linearly associated with increased incidence of severe PGD in a dose-dependent manner.

Perioperative statin use is associated with decreased incidence of primary graft dysfunction after lung transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after lung transplantation. Statins reduce the risk of chronic rejection after lung transplantation, but their effects on PGD are unknown. We hypothesized that perioperative statin therapy decreases the risk for PGD after lung transplantation. METHODS: We retrospectively reviewed records of all patients undergoing lung transplantation between January 1999 and December 2014 at the University of Virginia Health System. The primary outcome was PGD (grades 1-3). Secondary outcomes included grade 3 PGD, length of intensive care unit and hospital stay, and mortality. RESULTS: Of 266 patients who met final inclusion criteria, 138 (52%) were diagnosed with PGD. In-hospital mortality among patients with PGD was 6.5%. There were no deaths in patients without PGD (p < 0.001). PGD was diagnosed in 24 patients taking statins (34.8%) and in 114 patients (57.9%) who did not take statins (p = 0.001). After propensity score adjustments, perioperative statin use was independently associated with a reduced risk for PGD (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.20-0.84, p = 0.015) and reduced risk to develop grade 3 PGD (OR 0.42, 95% CI 0.18-0.94, p = 0.036). Other risk factors associated with PGD included intraoperative use of cardiopulmonary bypass (OR 3.74, 95% CI 1.75-8.02, p = 0.001) and positive donor smoking status (OR 2.27, 95% CI 1.18-4.35, p = 0.014). CONCLUSIONS: The results demonstrate that perioperative use of statins is independently associated with reduced risk for PGD after lung transplantation.

Akt: A Therapeutic Target in Hepatic Ischemia-Reperfusion Injury.

BACKGROUND: Liver transplantation is the second most common transplant procedure in the United States. A leading cause of post-transplantation organ dysfunction is I/R injury. During I/R injury, the serine/threonine kinase Akt is activated, stimulating downstream mediators to promote cellular survival. Due to the cellular effects of Akt, therapeutic manipulation of the Akt pathway can help reduce cellular damage during hepatic I/R that occurs during liver transplantation. OBJECTIVE: A full description of therapeutic options available that target Akt to reduce hepatic I/R injury has not been addressed within the literature. The purpose of this review is to illuminate advances in the manipulation of Akt that can be used to therapeutically target I/R injury in the liver. METHODS: An in depth literature review was performed using the Scopus and PubMed databases. A total of 75 published articles were utilized for this manuscript. Terminology searched includes a combination of "hepatic ischemia/reperfusion injury", "Akt/PKB", "preconditioning" and "postconditioning." RESULTS: Four principal methods that reduce I/R injury include hepatic pre- and postconditioning, pharmacological intervention and future miRNA/gene therapy. Discussed therapies used serum alanine aminotransferase levels, liver histology and phosphorylation of downstream mediators to confirm the Akt protective effect. CONCLUSION: The activation of Akt from the reviewed therapies has resulted in predictable reduction in hepatocyte damage using the previously mentioned measurements. In a clinical setting, these therapies could potentially be used in combination to achieve better outcomes in hepatic transplant patients. Evidence supporting reduced I/R injury through Akt activation warrants further studies in human clinical trials.

Effects of the Hypnotic Agent on Primary Graft Dysfunction After Liver Transplantation.

BACKGROUND: Morbidity and mortality rates in orthotopic liver transplantation have decreased in the past few years. Risk factors related to severe postoperative complications, such as primary graft dysfunction, still need to be analyzed. We evaluated the influence of the hypnotic agent used during anesthesia on primary graft dysfunction. METHODS: We performed a retrospective analysis of 419 consecutive patients who received a liver transplant between 2005 and 2013 in a single center. We analyzed the incidence of primary graft dysfunction (defined as alanine aminotransferase or aspartate aminotransferase levels higher than 1500 IU/L on the first 3 days after surgery) and if the hypnotic agent was associated with this event. RESULTS: The incidence of primary graft dysfunction was 42.2% (114 patients), similar in both groups (propofol group, 89 patients, 43.2% and sevoflurane group, 25 patients, 39.1%). In the multivariate analysis, we did not find any relationship between the hypnotic agent (propofol or sevoflurane) and early graft dysfunction. CONCLUSIONS: In our patients, we found no differences in the incidence of liver graft dysfunction according to the hypnotic used during transplantation. We can suggest that both drugs (sevoflurane and propofol) are equally safe in orthotopic liver transplantation.

The Oxidative and Inflammatory State in Patients with Acute Renal Graft Dysfunction Treated with Tacrolimus.

Objective. To determine the oxidative stress/inflammation behavior in patients with/without acute graft dysfunction (AGD) with Tacrolimus. Methods. Cross-sectional study, in renal transplant (RT) recipients (1-yr follow-up). Patients with AGD and without AGD were included. Serum IL-6, TNF-α, 8-isoprostanes (8-IP), and Nitric Oxide (NO) were determined by ELISA; C-reactive protein (CRP) was determined by nephelometry; lipid peroxidation products (LPO) and superoxide dismutase (SOD) were determined by colorimetry. Results. The AGD presentation was at 5.09 ± 3.07 versus 8.27 ± 3.78 months (p < 0.001); CRP >3.19 mg/L was found in 21 versus 19 in the N-AGD group (p = 0.83); TNF-α 145.53 ± 18.87 pg/mL versus 125.54 ± 15.92 pg/mL in N-AGD (p = 0.64); IL-6 2110.69 ± 350.97 pg/mL versus 1933.42 ± 235.38 pg/mL in N-AGD (p = 0.13). The LPO were higher in AGD (p = 0.014): 4.10 ± 0.69 µM versus 2.41 ± 0.29 µM; also levels of 8-IP were higher in AGD 27.47 ± 9.28 pg/mL versus 8.64 ± 1.54 pg/mL (p = 0.01). Serum levels of NO in AGD were lower 138.44 ± 19.20 µmol/L versus 190.57 ± 22.04 µmol/L in N-AGD (p = 0.042); antioxidant enzyme SOD activity was significantly diminished in AGD with 9.75 ± 0.52 U/mL versus 11.69 ± 0.55 U/mL in N-AGD (p = 0.012). Discussion. Patients with RT present with a similar state of the proinflammatory cytokines whether or not they have AGD. The patients with AGD showed deregulation of the oxidative state with increased LPO and 8-IP and decreased NO and SOD.

Heart Transplantation-The Pediatric Cardiac Critical Care Perspective.

OBJECTIVES: Although there have been tremendous advancements in the care of severe pediatric cardiovascular disease, heart transplantation remains the standard therapy for end-stage heart disease in children. As such, these patients comprise an important and often complex subset of patients in the ICU. The purpose of this article is to review the causes and management of allograft dysfunction and the medications used in the transplant population. DATA SOURCES: MEDLINE, PubMed, and Cochrane Database of systemic reviews. CONCLUSIONS: Pediatric heart transplant recipients represent a complex group of patients that frequently require critical care. Their immunosuppressive medications, while being vital to maintenance of allograft function, are associated with significant short- and long-term complications. Graft dysfunction can occur from a variety of etiologies at different times following transplantation and remains a major limitation to long-term posttransplant survival.

Potential Roles for C1 Inhibitor in Transplantation.

Complement is a major contributor to inflammation and graft injury. This system is especially important in ischemia-reperfusion injury/delayed graft function as well as in acute and chronic antibody-mediated rejection (AMR). The latter is increasingly recognized as a major cause of late graft loss, for which we have few effective therapies. C1 inhibitor (C1-INH) regulates several pathways which contribute to both acute and chronic graft injuries. However, C1-INH spares the alternative pathway and the membrane attack complex (C5-9) so innate antibacterial defenses remain intact. Plasma-derived C1-INH has been used to treat hereditary angioedema for more than 30 years with excellent safety. Studies with C1-INH in transplant recipients are limited, but have not revealed any unique toxicity or serious adverse events attributed to the protein. Extensive data from animal and ex vivo models suggest that C1-INH ameliorates ischemia-reperfusion injury. Initial clinical studies suggest this effect may allow transplantation of donor organs which are now discarded because the risk of primary graft dysfunction is considered too great. Although the incidence of severe early AMR is declining, accumulating evidence strongly suggests that complement is an important mediator of chronic AMR, a major cause of late graft loss. Thus, C1-INH may also be helpful in preserving function of established grafts. Early clinical studies in transplantation suggest significant beneficial effects of C1-INH with minimal toxicity. Recent results encourage continued investigation of this already-available therapeutic agent.